N quinoline 5 aminooxazoles

ABSTRACT

The present invention is concerned with compounds of Formula I: wherein R1 is heteroaryl and R2 is alkyl, aryl, or heteroaryl. Compounds of this invention exhibit central nervous system depressant properties.

United States Patent Von Strandtmann Feb. 20, 1973 [54] N QUINOLINE 5 AMINOOXAZOLES [75] Inventor: Maximilian Von Strandtmann,

Rockaway, NJ.

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22] Filed: June 9, 1971 [21] Appl. No.: 151,553

Related US. Application Data [62] Division of Ser. No, 843,762, July 22, 1969, Pat. No.

[52] US. Cl. ..260/287 R, 260/288 R, 424/258 [51] Int. Cl. ..C07d 85/44 [58] Field of Search ..260/307 R, 287 R, 288 R [56] References Cited UNITED STATES PATENTS 2,456,911 12/1948 Bruce ..260/287 R 2,494,083 1/1950 Bruce ..260/287 R 3,054,794 9/1962 Shapiro ..260/287 R 3,376,307 4/1968 Hyoen et a1. ..260/287 3,509,170 4/1970 Lent ..260/307 R Primary Examiner-Donald G. Daus Attorney-Albert H. Graddis et al.

[57] ABSTRACT The present invention is concerned with compounds of Formula 1:

wherein R is heteroaryl and R is alkyl, aryl, or heteroaryl.

Compounds of this invention exhibit central nervous system depressant properties.

4 Claims, No Drawings N QUINOLINE AMINOOXAZOLES This application is a divisional application of my copending application U.S. Ser. No. 843,762, filed July 22, 1969 now U.S. Pat. No. 3,624,097 granted Nov. 30, 1971.

The present invention relates to N-heteroaryl 5- aminooxazoles having the following structural formula:

wherein R is heteroaryl and R is lower alkyl, aryl, aralkyl, or heteroaryl.

In the above definitions for R and R the term heteroaryl encompasses the monocyclic and bicyclic hetero aromatic compounds having at least one hetero atom in the ring which may be either nitrogen, oxygen or sulfur. Representative heteroaryl radicals falling within this definition are, for example, pyridine, quinoline, pyrrole, indole, thiophene, benzimidazole, tetrazole, pyrymidine and the like. The term aryl denotes an aromatic radical, preferably of six to carbon atoms, such as for example, phenyl, tolyl and the like. The term aralkyl encompasses lower alkyl groups in which an aryl group as defined above is substituted for a hydrogen atom, such as for example, benzyl, phenethyl and the like. The term lower alkyl as used herein includes lower aliphatic hydrocarbons having one to five carbon atoms arranged in a straight carbon chain.

The compounds of this invention are useful in cases where a reduction in skeletal muscle spasm is indicated. For example, at a dose of 200 mg/kg intraperitoneally in laboratory animals, such as rats, the compounds of this invention produce a reduction in body tone lasting for 24 hours. Simultaneously, the motor activity and temperature are also decreased for a period of about 3 to 6 hours. Generally speaking,a dose range from 100 to 500 mg/kg is recommended to produce the desired reduction in motor activity. This dosage regimen may, of course, be varied according to body weight, sex, age, species of the mammal being treated as well as the severity of the condition being treated, by methods well known to the healing art.

In order to use these compounds, they are formulated with such standard pharmaceutical carriers, such as lactose, mannitol, dicalcium phosphate into dosage forms such as tablets, capsules and the like. They can also be combined with parenterally acceptable vehicles such as sesame oil, arachis oil and the like to form dosage forms suitable for parenteral injection.

According to the present invention, compounds of Type I are prepared by acylation of heteroarylamines of Type III with azlactones of Type I] followed by cyclodehydration of the intermediate compounds of type IV. The foregoing reaction is illustrated by the following schematic diagram:

N 0 RlNlL nmricocmmioom [I III in which R, and R are as previously defined.

Starting compounds III are readily available from commercial sources, for example, Aldrich Chemical Co. Azlactones of type II were prepared by the procedure described in Organic Syntheses, Vol. 47, p. 101 (John Wiley & Sons, Inc., New York, New York, 1967).

The following examples are included in order further to illustrate the invention.

EXAMPLE 1 N-[ (2-Quinolylcarbamoyl)methyl]benzamide Is prepared in the same manner as N-[(2-pyridyl carbamoyl) methyl1benzamide using 1 g. 2-aminoquinoline, 1.1 g. 2-phenyl-5-oxazolone and THF. The product is recrystallized from absolute EtOI-I. M.P. 2l8-219; yield: 1.7 g. (8l percent).

Anal. Calcd. for C H N O C, 70.80; H, 4.95; N,

13.76. Found: C, 70.98; H,5.00; N, 13.95.

EXAMPLE 3 2-[(Phenyl-5-oxazolyl)amino1pyridine 5 g. N-[(2-pyridyl carbamoyl)methyl]benzamide is added to g. of PPE and stirred for 45 hrs. The solution is poured onto 300 ml. of ice and water with stirring and basified with ammonium hydroxide. The

3 4 precipitate is filtered, washed with water and is 190l92', yield: 2.7 g. (72 percent). recrystallized from abs. ethanol. M.P. l69-l70', yield: Anal. Calcd. for C H N O: C, 75.24; H, 4.56; N, 1.5 g. (32 percent). 14.63.

Anal. Calcd. for C H N O: C, 70.87; H, 4.67; N, Found;C,75.15;H,4.56;N, 14.60.

17.71. 5 lclaim: FOuHdi l. A compound of the formula:

EXAMPLE 4 l0 Rani-{:1

wherein R is quinolyl and R is lower alkyl, or phenol.

2. A compound according to claim 1 which is 2- [(phenyl-5 -oxazolyl)amine quinoline.

3. A compound of the formula:

R NHCOCH NHCOIQ 2-[(Phenyl-5-oxazolyl)aminelquinoline a IS P p in the Same m a n net as 2[ (phenyl s ox wherein R 18 qumolyl and R is lower alkyl or phenyl.

azoiynaminemyridine using 3.7 g. of N [(2'quinoly1 A compound according to clairn 3 which is N-[(2- carbamoyl)methyl1benzamide and 75 g. of PPE. The qummylcarbamoynmethylwenzamlde' product is recrystallized from ethyl acetate. M.P. 

1. A compound of the formula: wherein R1 is quinolyl and R2 is lower alkyl, or phenol.
 2. A compound according to claim 1 which is 2-((phenyl-5-oxazolyl)amine)quinoline.
 3. A compound of the formula: R1NHCOCH2NHCOR2 wherein R1 is quinolyl and R2 is lower alkyl or phenyl. 